Nitriles have long been important not only as intermediates in organic synthesis, but many times of themselves. Recently, it was reported by S. A. Thompson, et al., in J. Am. Chem. Soc. 29, 104 (1985) that nitriles, especially analogs of enzyme substrates having a carboxamide group in its structure, can act as protease enzyme inhibitors. Protease enzymes play critically important roles in initiating, continuing or terminating a wide variety biological processes such as blood coagulation, complement activation, viral replication and in disease processes such as inflammatory and tissue degenerative diseases, tumor metastasis and the like. Other enzymes playing important roles in biological processes act on substrates having substituted amide groups in their structure. It is not unlikely that many enzymes acting on substrates having a substituted amide group may be inhibited or have the activity altered or modified by a substrate in which the amide group in the vicinity of a scissile bond is replaced with nitrile, i.e., by nitrile analogs of specific substrates.
The work of Thompson et al suggests that there may be infinite possibilities for nitriles corresponding to naturally occurring complex amides, acids, esters and other acid derivatives that should be investigated in connection with the search for new therapeutic agents which can be used to prevent, modify or reverse undesirable biological processes in the prevention and cure of diseases. Moreover, a number of compounds having a nitrile group together with another functional group are biologically active. A facile method for preparing nitriles is desired so that new inhibitors which may be one or more of the future drugs may not be overlooked because of difficulty of synthesis. Thus, a method of synthesis for nitriles, particularly a ready method for converting carboxamides to the corresponding nitriles would be highly desirable.
One convenient approach to the synthesis of nitriles is the dehydration of carboxamides. However, reagents which are generally employed to accomplish this dehydration are generally inappropriate in the synthesis of complex polyfunctional compounds which require mild conditions in their synthesis. the functional groups may be protected, protection of intermediates entails the extra steps of putting on a protecting group and of afterwards removing the protecting group. Not only are extra steps necessitated but at times the protection/deprotection procedure can adversely affect the desired structure. Recently, the use of liquid "diphosgene", trichloromethyl chloroformate, for transforming certain carboxamides to nitriles has been reported. (K. Mai et al, in Tetrahedron Letters, 1986 2203.) While the reagent is reported to be useful with a wide variety carboxamides, it has been found not to be usable with certain compounds such as those having an alcoholic hydroxyl group or even with simple heteroaromatic compounds such as nicotinamide. Moreover, the by-product of the reaction is a highly undesirable toxic gas, namely, phosgene. This would be especially undesirable where production of significant quantities of nitrile is desired. Further, the reagent is not seen to be useful for structures containing alcoholic hydroxyls or epoxide rings, the latter being especially sensitive to acidic reagents.
Methyl (carboxysulfamoyl)triethylammonium hydroxide inner salt ##STR1## often referred to as Burgess reagent, was used by Burgess and coworkers to convert tertiary and secondary alcohols to olefins and primary alcohols to urethanes. However other uses of this reagent are not known.